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Aryan Haratian, Katie Yensen, Jennifer A Bell, Laith K Hasan, Tara Shelby, Brandon Yoshida, Ioanna K Bolia, Alexander E Weber, Frank A Petrigliano USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, CA, USACorrespondence: Frank A PetriglianoUSC Epstein Family Center for Sports Medicine at Keck Medicine of USC, 1520 San Pablo Street, Suite 2000, Los Angeles, CA, 90033, USATel +1 323 442-5822Email fpetrigliano@gmail.comAbstract: Shoulder instability is a relatively common injury especially in the young athletic population and its surgical management continues to remain a controversial topic in sports medicine orthopedics. Anterior instability is the most common type encountered and is estimated to have an incidence rate of 0.08 per 1000 person–years in the general population; however, this figure is likely higher in the young athletic population. While in recent practice, arthroscopic surgery has become the new gold standard for management, reported failure rates as high as 26% and high recurrence rates in specific subpopulations such as young men in high collision sports have led to the consideration of alternative open procedures such as open Bankart repair, Latarjet, capsular shift, and glenoid bone grafting. These procedures may be preferred in specific patient subgroups such as young athletes involved in contact sports and those with Hill–Sachs defects and multidirectional instability, with postoperative recurrence rates of instability as low as 10%. The purpose of this review is to provide an overview of different open surgical techniques in the management of shoulder instability and summarize patient outcomes including recurrence rates for shoulder instability, return to sport, range of motion (ROM), muscle strength, and complications either individually by procedure or in comparison with other techniques, with special focus on their impact in the athletic population.Keywords: open shoulder stabilization, athletes, anterior instability, open Bankart repair, open Latarjet, open capsular shift

Ioanna K Bolia, Aryan Haratian, Jennifer A Bell, Laith K Hasan, Nima Saboori, Ryan Palmer, Frank A Petrigliano, Alexander E Weber USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, Los Angeles, CA, USACorrespondence: Alexander E WeberUSC Epstein Family Center for Sports Medicine at Keck Medicine of USC, 1520 San Pablo Street, Suite 2000, Los Angeles, CA, 90033, USAEmail weber.ae@gmail.comAbstract: Anterior cruciate ligament reconstructions (ACLR) are a relatively common procedure in orthopedic sports medicine with an estimated 130,000 arthroscopic operations performed annually. Most procedures are carried out on an outpatient basis, and though success rates of ACLR are as high as 95%, pain remains the most common postoperative complication delaying patient discharge, and thereby increasing the costs associated with patient care. Despite the success and relative frequency of ACLR surgery, optimal and widely accepted strategies and regimens for controlling perioperative pain are not well established. In recent years, the paradigm of pain control has shifted from exclusively utilizing opiates and opioid medications in the acute postoperative period to employing other agents and techniques including nerve blocks, intra-articular and periarticular injections of local anesthetic agents, NSAIDs, and less commonly, ketamine, tranexamic acid (TXA), sedatives, gabapentin, and corticosteroids. More often, these agents are now used in combination and in synergy with one another as part of a multimodal approach to pain management in ACLR, with the goal of reducing postoperative pain, opioid consumption, and the incidence of delayed hospital discharge. The purpose of this review is to consolidate current literature on various agents involved in the management of postoperative pain following ACLR, including the role of classically used opiate and opioid medications, as well as to describe other drugs currently utilized in practice either individually or in conjunction with other agents as part of a multimodal regimen in pain management in ACLR.Keywords: anterior cruciate ligament reconstruction, ACL, postoperative pain, patient outcomes, multimodal pain management

1. The metabolism of loxtidine (1-methyl-5-[3-[3-[(1-piperidinyl) methyl] phenoxy] propyl] amino-1H-1,2,4-triazole-3-methanol) was studied in freshly isolated rat, dog and human hepatocytes. Metabolism in vitro was comparable with previously available in vivo data in all three species with the marked species differences observed in vivo being reproduced in the hepatocyte model. 2. The major route for the metabolism of loxtidine by rat hepatocytes was N-dealkylation to form the propionic acid and hydroxymethyl triazole metabolites. A minor metabolic route was the oxidation of loxtidine to a carboxylic acid metabolite. The major route of metabolism for loxtidine in dog hepatocytes was glucuronidation with oxidation to the carboxylic acid metabolite being of minor importance. Incubation of loxtidine with human hepatocytes resulted in the drug remaining largely unchanged but with the carboxylic acid metabolite being produced in minor amounts. 3. In vitro studies were undertaken with rat, dog and human hepatocytes to determine the Michaelis-Menten parameters Vmax and Km for the sum of all the metabolic pathways. These kinetic parameters were used to calculate the intrinsic clearance of loxtidine. Using appropriate scaling factors, the predicted in vivo hepatic clearance was then calculated. The predicted intrinsic clearances were 51.4 +/- 12.4, 8.0 +/- 0.8 and 1.0 +/- 0.6 ml/min/kg for rat, dog and human hepatocytes respectively. These data were then used to calculate hepatic clearances of 24.5, 3.1 and 0.2 ml/min/kg for rat, dog and man respectively. 4. In vivo hepatic and intrinsic clearances for loxtidine were determined in rat, dog and human volunteers. The hepatic clearances of loxtidine were 26.6, 6.6 and 0.4 ml/min/kg in rat, dog and man respectively and intrinsic clearances were 58.5, 18.6 and 2.0 ml/min/kg in rat, dog and man respectively. 5. The present studies demonstrate that the hepatocyte model may be a valuable in vitro tool for predicting both qualitative and quantitative aspects of the metabolism of a drug in animals and man at an early stage of the drug development process.

We have previously shown that redox phenomena regulate the function of the NMDA receptor in the brain and that ascorbic acid (AA) behaves as a receptor antagonist. Here we examined the potential neuroprotective effects of AA against toxicity induced by NMDA and glutamate in rat cerebral cortical neurones in cultures. AA completely protected against injury induced by 100 microM NMDA and markedly reduced cell death induced by 500 microM NMDA or 50 microM glutamate. Dehydroascorbic acid (DHAA) did not provide significant neuroprotection. Hence, we propose that AA may serve in the CNS as a neuroprotectant.

1. Freshly isolated hepatocytes from rat and dog have been evaluated as a model for the metabolism of ranitidine in vivo. 2. Isolated hepatocytes from the male and female dog and male Wistar and random hooded rat metabolized ranitidine to ranitidine N-oxide, ranitidine S-oxide, desmethylranitidine and two unidentified minor metabolites. The furoic acid metabolite of ranitidine, previously reported to be a minor metabolite in vivo in rat and dog, was not detected in hepatocytes from either species. 3. The kinetics for ranitidine metabolism in hepatocytes were monophasic for the formation of the three major metabolites in dog and Wistar rat and for N-demethylation of ranitidine in the random hooded rat, but biphasic in this latter strain for the N- and S-oxidation of ranitidine. 4. Ranitidine N-oxide was reduced to ranitidine by Wistar rat hepatocytes but not by hepatocytes from the random hooded rat or dog. Ranitidine S-oxide was metabolized by hepatocytes from both species to one of the unidentified metabolites but was not reduced to ranitidine in either species. Desmethylranitidine was not a substrate for metabolism in hepatocytes from either species. 5. The relative quantitative importance of ranitidine N-oxide, ranitidine S-oxide and desmethylranitidine produced by the hepatocytes was consistent with the profiles of these three metabolites in vivo in rat and dog. The results confirm the value of isolated hepatocytes as a predictive model for in vivo drug metabolism.

1. A comparative study of the kinetics of the O-deethylation of 7-ethoxycoumarin has been carried out in freshly isolated rat, dog and human hepatocytes. 2. Biphasic kinetics were observed for all three species with apparent Km and Vmax values of 11.5, 2.2 and 3.9 microM and 0.30, 0.21, 0.007 nmol/min/10(6) cells from rat, dog and man, respectively, for the high affinity-low capacity component, and 560, 40, 470 microM and 1.52, 0.74, 0.057 nmol/min/10(6) cells, respectively, for the low affinity-high capacity component. 3. These observed kinetic parameters in hepatocytes from rat and man were similar to published values for microsomes for the same two species. 4. Values for intrinsic clearance of 7-ethoxycoumarin for the three species calculated from the Km and Vmax data were 152, 631 and 6 ml/min/kg for rat, dog and human hepatocytes, respectively. These intrinsic clearance values predict that 7-ethoxycoumarin would be subject to a high hepatic clearance in rat and dog, and low hepatic clearance in man. These values are supported by published data on rat which show that 7-ethoxycoumarin is subject to high clearance.

The objective of this study was to assess the etiology of lateral rectus palsies in patients undergoing lumbar myelograms with Iopamidol (Isovue; ER Squibb and Sons, Princeton, NJ, USA; Niopam, E Merc, UK.). An audit of the departmental orthoptic record revealed two patients who had suffered abducens palsies after myelograms. A further search revealed three additional patients who had suffered similar complications. The incidence of abducens palsy in patients undergoing myelography with the contrast agent Iopamidol was found to be 1 in 500 in around 2,500 myelograms performed under standard conditions. It would appear that lateral rectus palsy in myelography is the result of the lumbar puncture, the neurotoxic effect of the contrast agent, or a combination of the two in patients with an already compromised neurophysiologic state. This is the first series to associate this problem with Iopamidol. Although usually a serious neurologic symptom, when associated with contrast myelography using Iopamidol it is important to appreciate that such symptoms usually resolve of their own accord.

Evidence on systemic inflammation as a risk factor for future depression is inconsistent, possibly due to a lack of regard for persistency of exposure. We examined whether being inflamed on multiple occasions increases risk of new depressive symptoms using prospective data from a population-based sample of adults aged 50 years or older (the English Longitudinal Study of Ageing). Participants with less than four of eight depressive symptoms in 2004/05 and 2008/09 based on the Eight-item Centre for Epidemiologic Studies Depression scale were analysed. The number of occasions with C-reactive protein ⩾3 mg l-1 over the same initial assessments (1 vs 0 occasion, and 2 vs 0 occasions) was examined in relation to change in depressive symptoms between 2008/09 and 2012/13 and odds of developing depressive symptomology (having more than or equal to four of eight symptoms) in 2012/13. In multivariable-adjusted regression models (n=2068), participants who were inflamed on 1 vs 0 occasion showed no increase in depressive symptoms nor raised odds of developing depressive symptomology; those inflamed on 2 vs 0 occasions showed a 0.10 (95% confidence intervals (CIs)=-0.07, 0.28) symptom increase and 1.60 (95% CI=1.00, 2.55) times higher odds. In further analyses, 2 vs 0 occasions of inflammation were associated with increased odds of developing depressive symptoms among women (odds ratio (OR)=2.75, 95% CI=1.53, 4.95), but not among men (OR=0.70, 95% CI=0.29, 1.68); P-for-sex interaction=0.035. In this cohort study of older adults, repeated but not transient exposure to systemic inflammation was associated with increased risk of future depressive symptoms among women; this subgroup finding requires confirmation of validity.

The Hireceptor antagonist cimetidine inhibits aminopyrineN-demethylation activity of rat liver microsomes and prolongs sleeping times in hexobarbital treated rats (Puurunen & Pelkonen, 1979). In man, cimetidine interacts with warfarin (Flind et al., 1978; Serlin el al., 1979), antipyrine (Serlin et al., 1979) and diazepam (Klotz et al., 1979). The results may be explained by the interaction of cimetidine with the microsomal cytochrome P-450 linked mono-oxygenase system (Puurunen & Pelkonen, 1979). Rend% et al. (1979) have shown that cimetidine interacts with oxidized liver microsomes to produce a ‘type 11’ spectral change characteristic of lipophilic nitrogenous bases. Ranitidine and AH 18801 are novel H,-receptor antagonists which do not contain the imidazole nucleus regarded essential for H,-receptor blockade (Ganellin et al., 1976). Ranitidine is effective in the treatment of duodenal ulcer in man (Saunders et al., 1980). We have compared the interactions of cimetidine, AH 18801 and ranitidine with drug-metabolizing enzymes in vitro and in uiuo. Liver microsomal fractions from male Wistar (A and H strain) albino rats (350-400g) were prepared by differential centrifugation. Difference spectra were obtained for cimetidine, ranitidine and AH1 8801 by using a Pye Unicam SP8-100 UV/VIS spectrophotometer. Each cuvette contained 2.5 ml of microsomal suspension (2.5 mg of protein/ml). Methanolic solutions of each compound were added to the sample cuvette; an equal volume of methanol was added to the reference cuvette. The final concentrations of each compound were 0.05-2.93 mM.. The difference in absorption (AA) between the peak and trough in each spectrum divided by the concentration of compound was plotted against AA. The spectral dissociation constant ( K 3 was obtained from the reciprocal of the slope of this line. Each compound was given orally at doses of 15,45, 115 and 135 mg/kg body wt. to male Wistar (A and H strain) albino rats (90-1 30 g) 1 h before intraperitoneal pentobarbitone sodium (40mg/kg body wt.). The sleeping times were measured as the time between loss and subsequent recovery of righting reflex. Significant differences between vehicle control and test groups were assesed by the Mann-Whitney U test (Siegel, 1956). The binding spectra of each compound showed a minimum absorbance at 390nm and a maximum at 420nm, indicating ligand interaction between these compounds and ferrihaemoprotein (Schenkman et al., 1967). The structural formulae, lipophilicity (log P), spectral dissociation constants and doses which produced significant increases in sleeping time are shown in Table 1. Two spectral dissociation constants (K,I and K,2) for each compound were obtained indicating high and low affinity sites. The K,I values indicate that the affinity for cytochrome P-450 increases in the order ranitidine, AH 18801 then cimetidine. Cimetidine e 4 5 m g / k g body wt.) and AH 18801 (2 1 15 mg/kg body wt.) significantly increased sleeping times; ranitidine had no significant effect over the dose range studied. From e.p.r. studies, Rendic et al. (1979) were unable to determine unambiguously which hetero-atom of cimetidine was co-ordinated to the iron of cytochrome P-450. The absence of a cyanoguanidine group in ranitidine may be the reason for ranitidine not being as strongly bound as cimetidine and AH1 8801 to cytochrome P-450. The affinity of ligand binding is affected by the hydrophobic interaction of the aliphatic or aromatic groups in a molecule (Ullrich er al., 1975). The lower binding affinity of ranitidine may, therefore, be a function of its lower lipophilicity (logP = 0.20) compared with that of cimetidine (log P=0.45) or AH 18801 (log P= 1.19). The results of these studies suggest that, in man, ranitidine will not inhibit microsomal drug metabolism.